PROTAC-Based Strategies in Neurodegenerative Diseases: Challenges and Perspectives

TARGETED PROTEIN DEGRADATION WITH PROTACS IN CANCER THERAPY: MECHANISMS, CLINICAL ADVANCES, CHALLENGES, AND FUTURE PERSPECTIVES

This thorough analysis investigates the molecular basis of PROTAC technology, tracking its progression from an elegant intellectual notion to a clinically approved treatment platform and provides a detailed survey of the current clinical landscape.

In situ self-assembly of PROTACs for precision cancer therapy.

Proteolysis-targeting chimeras (PROTACs) are heterobifunctional molecules that degrade pathogenic proteins via the ubiquitin-proteasome system. Their event-driven mechanism enables targeting of traditionally undruggable proteins and overcomes acquired resistance through complete protein degradation. Despite these advantages in cancer therapy, clinical translation of PROTACs is hampered by high molecular weight, poor solubility, off-target effects, and the hook effect. To address these challenges, integrating bioorthogonal in situ self-assembly of PROTACs with advanced nanodelivery platforms has emerged as a promising strategy to enhance delivery efficiency, enable spatiotemporally controlled protein degradation, and reduce toxicity. This review systematically outlines design and construction strategies for in situ self-assembling PROTACs, highlighting recent advances in nanodelivery systems that improve solubility, bioavailability, and degradation efficacy while mitigating off-target effects and the hook effect. Finally, we discuss current challenges and future perspectives for PROTACs-based precision cancer therapy.

Targeted protein degradation: bridging chemical biology and clinical translation.

An overview of the developmental trajectory of the TPD field is provided and how diverse modalities can be leveraged to address intracellular, membrane-associated, and extracellular protein targets are discussed.

Leveraging Supramolecular Polymers to Induce the Targeted Protein Degradation of α-Synuclein

Post-translational chemical modification of E3 ligase for efficient target protein degradation.

This work reports the first ligand-directed chemical strategy that converts transient PROTAC-mediated ternary complex formation into binary target recognition via post-translational chemical modification of an E3 ligase, and believes it could provide a platform for next-generation targeted protein degraders to overcome the current limitation of PROTAC approach.

Stimulating proteasomal degradation in human proteinopathies.

The ubiquitin-proteasome system (UPS) comprises hundreds of proteins that orchestrate ubiquitin-dependent proteasomal degradation and represents a powerful therapeutic target for modulating intracellular protein turnover. Due to its central role in preventing the accumulation of misfolded and dysfunctional proteins, enhancing or suppressing UPS activity offers clinical potential across a wide spectrum of diseases. While oncology has successfully capitalized on this vulnerability through the development of proteasome inhibitors for the treatment of hematological malignancies, efforts to generate clinically relevant UPS activators have progressed more slowly. Bridging this therapeutic gap could be particularly beneficial for neurodegenerative diseases and other proteinopathies, where accelerating the removal of misfolded and aggregation-prone proteins may help counteract their progressive accumulation and delay, or prevent the onset of symptoms. In this review, we summarize the progress made so far toward finding strategies to boost UPS function through genetic or small-molecule interventions.